Soursop-Derived Gut Metabolites Restore Adipose Metabolic Homeostasis and Attenuate Fructose-Induced Adipotoxicity: Mechanistic Insights into the Soursop-Gut-Adipose Axis.

Adipotoxicity is a major contributor to insulin resistance and type 2 diabetes, and increasing evidence highlights the gut-adipose axis as a promising therapeutic target. Soursop (Annona muricata) is rich in phytochemicals that can be biotransformed by the gut microbiota into bioactive metabolites with metabolic benefits. The present study investigated whether metabolites generated by in vitro fecal fermentation of soursop fruit (SWSF) and peel (SWSFP) protect against fructose-induced adipotoxicity. SWSF and SWSFP were fermented with rat fecal microbiota, and the resulting metabolites were evaluated in an ex vivo fructose-induced adipotoxicity model using perigonadal white adipose tissue. Activities of enzymes involved in glucose metabolism, the polyol pathway, glutathione metabolism, glyoxalase-1 activity, purinergic signaling, and inflammatory lipid metabolism were determined. GC-MS-based metabolomics and pathway enrichment analyses were performed on fecal and adipose tissues. Soursop fermentation significantly remodeled the fecal metabolome, enriching metabolites associated with fatty acid metabolism, glycerolipid metabolism, β-oxidation, sterol metabolism, and arachidonic acid metabolism. Fructose-induced adipotoxicity disrupted glucose metabolism, activated the polyol pathway, impaired glutathione metabolism and glyoxalase-1 activity, suppressed ATPase and ENTPDase activities, and elevated 5-LOX and 12/15-LOX activities. Treatment with soursop-enriched fecal metabolites significantly reversed these alterations in a dose-dependent manner. Adipose metabolomics further demonstrated restoration of pathways associated with fatty acid biosynthesis, mitochondrial β-oxidation, glycerolipid metabolism, steroid biosynthesis, and polyunsaturated fatty acid metabolism, indicating improved lipid homeostasis and reduced inflammatory lipid signaling. SWSF and SWSFP generally exhibited greater metabolic protection than the reference antioxidant compound, gallic acid. Soursop-derived gut metabolites attenuate fructose-induced adipotoxicity by coordinately restoring glucose metabolism, redox homeostasis, carbonyl detoxification, purinergic signaling, and lipid metabolism through the gut-adipose axis. These results suggest soursop as a potential functional food for preventing and managing adipose tissue dysfunction and metabolic disorders.